Pouneh K. Fazeli

Increased Bone Marrow Fat in Anorexia Nervosa

CONTEXT Although women with anorexia nervosa (AN) have severe depletion of body fat, a paradoxical increase in bone marrow fat has been described. Recent data suggest that marrow fat measured by 1H-magnetic resonance spectroscopy (MRS) in combination with bone mineral density (BMD) may be more valuable than either parameter alone in detecting bone weakness. OBJECTIVE The objective of the study was to investigate the effect of AN on accumulation of marrow fat in spine and femur using 1H-MRS and the relationship between marrow fat, BMD, and body composition in subjects with AN and normal-weight controls. DESIGN This was a cross-sectional study. SETTING The study was conducted at a referral center. PATIENTS Patients included 10 women with AN (29.8 +/- 7.6 yr) and 10 normal-weight age-matched women (29.2 +/- 5.2 yr). INTERVENTIONS There were no interventions. MAIN OUTCOMES MEASURE Marrow fat content of the fourth lumbar vertebra and femur measured by 1H-MRS. BMD of spine and hip measured by dual-energy x-ray absorptiometry. RESULTS Subjects with AN had higher marrow fat at the fourth lumbar vertebra and femur compared with controls (P = 0.004-0.01). There was an inverse correlation between marrow fat of L4 and femur and BMD of the spine and hip (r = -0.56 to -0.71, P = 0.01-0.0002) and body mass index and sc adipose tissue of the thigh (r = -0.49 to -0.71, P = 0.03-0.0007). There was an inverse correlation between femur marrow fat and sc and total abdominal adipose tissue (r = -0.53 to -0.67, P = 0.003-0.03). CONCLUSION Women with AN have greater lumbar and femoral marrow fat than controls, and marrow fat correlates inversely with BMD. This paradoxical increase in marrow fat at a time when sc and visceral fat are markedly reduced raises important questions about functional consequences of this process.

Marrow fat and bone--new perspectives.

CONTEXT There is growing interest in the relationship between bone mineral density, bone strength, and fat depots. Marrow adipose tissue, a well-established component of the marrow environment, is metabolically distinct from peripheral fat depots, but its functional significance is unknown. OBJECTIVE In this review, we discuss animal and human data linking the marrow adipose tissue depot to parameters of bone density and integrity as well as the potential significance of marrow adipose tissue in metabolic diseases associated with bone loss, including type 1 diabetes mellitus and anorexia nervosa. Potential hormonal determinants of marrow adipose tissue are also discussed. CONCLUSIONS We conclude that whereas most animal and human data demonstrate an inverse association between marrow adipose tissue and measures of bone density and strength, understanding the functional significance of marrow adipose tissue and its hormonal determinants will be critical to better understanding its role in skeletal integrity and the role of marrow adipose tissue in the pathophysiology of bone loss.

Bone Marrow Adipose Tissue Is an Endocrine Organ that Contributes to Increased Circulating Adiponectin during Caloric Restriction

The adipocyte-derived hormone adiponectin promotes metabolic and cardiovascular health. Circulating adiponectin increases in lean states such as caloric restriction (CR), but the reasons for this paradox remain unclear. Unlike white adipose tissue (WAT), bone marrow adipose tissue (MAT) increases during CR, and both MAT and serum adiponectin increase in many other clinical conditions. Thus, we investigated whether MAT contributes to circulating adiponectin. We find that adiponectin secretion is greater from MAT than WAT. Notably, specific inhibition of MAT formation in mice results in decreased circulating adiponectin during CR despite unaltered adiponectin expression in WAT. Inhibiting MAT formation also alters skeletal muscle adaptation to CR, suggesting that MAT exerts systemic effects. Finally, we reveal that both MAT and serum adiponectin increase during cancer therapy in humans. These observations identify MAT as an endocrine organ that contributes significantly to increased serum adiponectin during CR and perhaps in other adverse states.

Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues

Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal ‘regulated’ MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal ‘constitutive’ MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism.

Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa

OBJECTIVE To (i) compare fracture prevalence in adolescent females with anorexia nervosa (AN) versus normal-weight controls and (ii) examine whether reductions in areal bone mineral density (aBMD) predict fracture risk in females with AN. METHOD Four-hundred eighteen females (310 with active AN and 108 normal-weight controls) 12- to 22-years-old were studied cross-sectionally. Lifetime fracture history was recorded by a physician during participant interviews. Body composition and aBMD measurements of the whole body, whole body less head, lumbar spine, and hip were assessed by dual-energy X-ray absorptiometry, and bone mineral apparent density (BMAD) was calculated for the lumbar spine. RESULTS Participants with AN and normal-weight controls did not differ for chronological age, sexual maturity, or height. The lifetime prevalence of prior fracture was 59.8% higher in those with AN as compared to controls (31.0% vs. 19.4%, p = 0.02), and the fracture incidence rate peaked in our cohort after the diagnosis of AN. Lower aBMD and lumbar BMAD were not associated with a higher prevalence of fracture in the AN or control group on univariate or multivariate analyses. Compared to controls, fracture prevalence was significantly higher in the subgroup of girls with AN who had normal aBMD or only modest reductions of aBMD (Z-scores > -1 or -1.5). DISCUSSION This is the first study to show that the risk of fracture during childhood and adolescence is significantly higher in patients with AN than in normal-weight controls. Fracture prevalence is increased in this cohort of participants with AN even without significant reductions in aBMD.

Food motivation circuitry hypoactivation related to hedonic and nonhedonic aspects of hunger and satiety in women with active anorexia nervosa and weight-restored women with anorexia nervosa

BACKGROUND Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight-restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait. METHODS We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal. RESULTS We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease. LIMITATIONS Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included. CONCLUSION Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of foods reward value and integration of these with interoceptive signalling of ones internal state of well-being, with important relations between brain activity and homeostatic and hedonic aspects of appetite. Our findings give novel evidence of disruption in neurobiological circuits and stress the importance of examining both state and trait characteristics in the investigation of brain phenotypes in individuals with anorexia nervosa.

Preadipocyte Factor-1 Is Associated with Marrow Adiposity and Bone Mineral Density in Women with Anorexia Nervosa

CONTEXT Despite having low visceral and sc fat depots, women with anorexia nervosa (AN) have elevated marrow fat mass, which is inversely associated with bone mineral density (BMD). Adipocytes and osteoblasts differentiate from a common progenitor cell, the human mesenchymal stem cell. Therefore, understanding factors that regulate this differentiation process may provide insight into bone loss in AN. OBJECTIVE The objective of the study was to investigate the relationship between preadipocyte factor-1 (Pref-1), a member of the epidermal growth factor-like family of proteins and regulator of adipocyte and osteoblast differentiation, and fat depots and BMD in AN. DESIGN This was a cross-sectional study. SETTING The study was conducted at a clinical research center. PATIENTS Patients included 20 women with AN (26.8 +/- 1.5 yr) and 10 normal-weight controls (29.2 +/- 1.7 yr). INTERVENTIONS There were no interventions. MAIN OUTCOMES MEASURE Pref-1, leptin, IGF-I, IGF binding protein (IGF-BP)-2 and estradiol levels were measured. BMD of the spine and hip was measured by dual-energy x-ray absorptiometry. Marrow fat content of the L4 vertebra and femur was measured by (1)H-magnetic resonance spectroscopy. RESULTS Pref-1 levels were significantly higher in AN compared with controls (P = 0.01). There was a positive correlation between Pref-1 and marrow fat of the proximal femoral metaphysis (R = 0.50, P = 0.01) and an inverse association between leptin and L4 marrow fat (R = -0.45, P < 0.05). There was an inverse association between Pref-1 and BMD of both the anteroposterior spine and lateral spine (R = -0.54, P = 0.003; R = -0.44, P = 0.02, respectively). CONCLUSIONS Pref-1 is elevated in AN. Pref-1, IGF-I, IGF-BP2 and leptin are associated with marrow adiposity and BMD.

Young women with cold-activated brown adipose tissue have higher bone mineral density and lower Pref-1 than women without brown adipose tissue: a study in women with anorexia nervosa, women recovered from anorexia nervosa, and normal-weight women.

CONTEXT Anorexia nervosa (AN) is associated with depletion of body fat, loss of bone mineral density (BMD), and impaired thermogenesis. Brown adipose tissue (BAT) is lower in obese individuals and decreases during aging. Recent studies have suggested a link between BAT and bone metabolism. OBJECTIVE Our objective was to investigate the presence and quantity of BAT in patients with AN, recovered AN (AN-R), and normal-weight controls and to study the relationship between BAT and BMD and body composition and investigate hormonal predictors of BAT. DESIGN AND SETTING This was a cross-sectional study at a clinical research center. PATIENTS Patients included 15 women: five with AN (mean age 30 ± 6.3 yr), five AN-R, and five healthy nonobese controls of comparable age. MAIN OUTCOME MEASURES Cold-activated BAT was determined by fluorodeoxyglucose-positron emission tomography/computed tomography. BMD of total-body, spine, and hip, fat and lean mass was determined by dual-energy x-ray absorptiometry. Single-slice magnetic resonance imaging at L4 was done for abdominal fat compartments, and preadipocyte factor-1 (Pref-1), T₃, and T₄ were measured. RESULTS Within the AN group, one of five; in the AN-R group, two of five; and in the healthy nonobese control group, four of five subjects were BAT positive. Subjects were divided into groups based on the presence (n = 7) or absence (n = 8) of BAT. Both groups were of comparable age and body mass index. Women with BAT had higher total-body BMD, higher T₃, and lower Pref-1 compared with women without BAT. There was a positive correlation between BAT and BMD that remained significant after controlling for disease status and body mass index. CONCLUSION Young women with AN have low cold-activated BAT, which may be due to impaired BAT thermogenesis. Young women with BAT have higher BMD and lower Pref-1 compared with women without BAT, suggesting that BAT may be involved in the regulation of stem cell differentiation into the bone lineage at the expense of adipogenesis.

Effects of Recombinant Human Growth Hormone in Anorexia Nervosa: A Randomized, Placebo-Controlled Study

CONTEXT Anorexia nervosa (AN), a state of chronic nutritional deprivation, is characterized by GH resistance with elevated GH levels and decreased levels of IGF-I. The effects of supraphysiological recombinant human GH (rhGH) on GH resistance in AN are not currently known. OBJECTIVE The aim was to investigate whether supraphysiological rhGH increases IGF-I levels in AN. DESIGN AND SETTING We conducted a randomized, placebo-controlled study in a Clinical Research Center. PATIENTS We studied 21 women with AN, 10 (mean age, 28 ± 2.1 yr) treated with rhGH and 11 (mean age, 29.2 ± 2.6 yr) treated with placebo. INTERVENTIONS rhGH (mean maximum daily dose, 1.4 ± 0.12 mg/d) or placebo was administered to patients for 12 wk. MAIN OUTCOME MEASURES IGF-I, N-terminal propeptide of type 1 procollagen, type I collagen C-telopeptide, glucose, and insulin levels were measured at wk 0, 1, 2, 3, 4, 8, and 12; C-terminal propeptide of type 1 procollagen, leptin, and free fatty acid levels were measured at wk 0 and 12. Body composition, including total fat and lean mass, was measured by dual-energy x-ray absorptiometry at wk 0 and 12. RESULTS IGF-I levels did not differ between the groups at baseline or after treatment (median after 12 wk-rhGH, 124 ng/ml, interquartile range, 94.5, 170.3; vs. placebo, 85.5 ng/ml, interquartile range, 62, 139; P = 0.3). Similarly, changes in glucose, insulin, free fatty acids, and bone markers did not differ between the groups. Total fat mass and percentage fat mass (rhGH, -2.5 ± 0.6%, vs. placebo, 2.2 ± 1.1%; P = 0.004) decreased significantly in the rhGH group compared to placebo despite comparable weight. CONCLUSIONS Supraphysiological rhGH administration decreases fat mass in AN without increasing IGF-I levels, supporting the role of GH as a mediator of lipolysis independent of IGF-I.

Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa.

Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat in women who have recovered from AN (AN‐R). We also studied the relationship between preadipocyte factor (Pref)‐1—a member of the EGF‐like family of proteins and regulator of adipocyte and osteoblast differentiation—and fat depots and BMD in AN‐R compared with women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years [mean ± SEM]) and 15 normal‐weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by 1H‐magnetic resonance spectroscopy; BMD of the spine, hip, and total body by DXA; and serum Pref‐1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN‐R compared with AN (p = 0.03) and was comparable to levels in HC. Pref‐1 levels were also significantly lower in AN‐R compared with AN (p = 0.02) and comparable to levels in healthy controls. Although Pref‐1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = −0.71; p = 0.004). Therefore, we have shown that MAT and Pref‐1 levels decrease with recovery from AN. Our data suggest that Pref‐1 may have differential effects in states of nutritional deprivation compared with nutritional sufficiency.